The ultimate goal of this project is to develop immunization procedures which will reduce morbidity and mortality due to influenza virus infection. The first step has been to understand the host defense mechanisms responsible for protection, and this was largely accomplished during the previous grant period. In order to do this it was necessary to separate considerations of prevention and recovery as well as considerations of rhinotracheitis and viral pneumonia. Serum antibody mediates prevention of viral pneumonia, but not rhinotracheitis. Local sIgA antibody is probably responsible for prevention of rhinotracheitis. Recovery is mediated by CMI, but serum antibody helps spread recovery. CMI is also responsible for heterotypic immunity which restricts the speed of new species of influenza virus through the respiratory tract and thereby reduces the severity of illness. The next step will be to develop more effective immunization procedures that stimulate anti-influenza serum antibody, and sIgA antibody in animals which model the following 3 immune states: 1) virgins, 2) animals previously infected with a different influenza type A species (heterotypic), and 3) animals previously infected with the same influenza type A species (homotypic). We will use virgin mice, heterotypic mice, and homotypic mice for evaluating the ability of a variety of vaccines to prevent viral pneumonia and rhinotracheitis. The vaccines to be tested will include the standard zonally purified whole virus vaccine, liposomes containing the hemagglutinin and neuraminidase, hemagglutinin-specific synthetic peptides coupled to protein carriers and recombinant vaccinia virus which contains various influenza genes. Both local and systemic administration will be evaluated. The use of recombinant vaccinia virus is potentially promising for the protection of children against a wide variety of diseases (e.g., measles, malaria, polio, and tetanus) and this approach may be of particular importance in the Third World. The use of the vaccinia/influenza recombinant in the mouse model allows us to investigate some important questions regarding new immunization procedures involving the use of recombinant vaccina virus. For example, will it be possible to get an immune response in the face of passive antibody. The recombinant virus will also be useful for elucidating the role of specific influenza viral antigens in eliciting host defense.